This invention generally pertains to heterocyclic carbon compounds having drug and bio-affecting properties and to their preparation and use. In particular, the invention is concerned with 1,4-disubstituted piperazine derivatives wherein one substituent is a pyrimidin-2-yl ring and the other is a 1-pyrrolidin-2-one ring linked by a bridging moiety to the piperazine nitrogen atom. The compounds of this invention are applicable in the treatment of various senile dementias affecting adults.
The clinical aspects of various senile dementias as well as the problems they cause in the affected adult subject are well known to those skilled in the art. One will also appreciate that various drug treatments of this disorder are currently under study. Among such drugs are a class of drugs known as nootropic agents or, more commonly, cognition enhancers; some of which are currently undergoing clinical evaluation in patients diagnosed as having Alzheimer's disease, a serious and fairly common CNS disorder. Chemically, these drugs under clinical study are members of a class of N-substituted 2-pyrrolidinone derivatives of structure 1. ##STR2## a: X=H; R=--CH.sub.2 CONH.sub.2 (piraacetam) b: X=OH; R=--CH.sub.2 CONH.sub.2 (oxiracetam)
c: X=H; R=--CH.sub.2 CONH[CH.sub.2 ].sub.2 N[CH(CH.sub.3).sub.2 ].sub.2 (pramiracetam) PA1 d: X=H; ##STR3## Preliminary clinical results with this class of agents, exemplified by structures 1a-d, indicates that these drugs may have some beneficial effects in treating senile dementias. PA1 R=C.sub.1-4 alkyl, specifically methyl. PA1 R=C.sub.1-3 alkyl PA1 X.sup..crclbar. =a pharmaceutically acceptable anion. PA1 R.sup.1 is an allyl, cinnamyl or p-methoxybenzyl group. PA1 Wu, et al., U.S. Pat. No. 3,717,634 patented Feb. 20, 1973. Temple, U.S. Pat. No. 4,423,049 patented Dec. 27, 1983. New and Yevich, pending application Ser. No. 531,519, filed Sept. 12, 1983. PA1 R.sup.2 is hydrogen, lower alkyl, unsubstituted aryl or aryl optimally substituted at one or more ring positions with lower alkyl, halogen, --CF.sub.3, --CN, --NO.sub.2, ##STR13## --NR.sup.3.sub.2, --CO.sub.2 R.sup.4, or OR.sup.5, with R.sup.3 being H or lower alkyl, R.sup.4 being R.sup.3, phenyl or phenalkyl, and R.sup.5 being R.sup.4 ; and PA1 X is a chemical bond, ##STR14## has been prepared. Compounds of this series can be incorporated into pharmaceutical compositions for use in adult subjects afflicted with senile dementias. A number of these compounds have been tested and display cognition enhancing action and/or mild CNS stimulation. These actions have been demonstrated by EEG and prevention of ECS-induced amnesia in rats and maze-testing of aged rats. PA1 R.sup.2 is hydrogen, lower alkyl, unsubstituted aryl or aryl optimally substituted at one or more ring positions PA1 X is a chemical bond, ##STR17## By lower alkyl is meant that these groupings contain from one to four carbon atoms. Halogen means F, Cl, Br, or I and aryl means phenyl or naphthyl. For preferred compounds, R.sup.1 and R.sup.2 are hydrogen, and for the most preferred compound, X is a chemical bond.
Related art may be viewed in light of the following general structural formula 2 ##STR4## in which A is a bridging moiety such as alkyl, alkanoyl, alkylamidoalkyl, and the like; and B is a substituent group.
In Great Britain No. 2,023,594, a series of 1-substituted alkyl-4-(3-trifluoromethylthiophenyl)-piperazines were disclosed as being useful in treatment of anxiety and depression. Specifically disclosed were compounds of structurre 3. ##STR5## wherein n=2, 3.
U.S. Pat. No. 4,145,347, issued Mar. 20, 1979 to L'Italien, et al. disclosed a series of N-(substituted-aminoalkyl)-2-oxo-1-pyrrolidine acid amides as cognition activators potentially useful in treating patients suffering from senility. The most relevant compounds disclosed in this patent have structural formula 4. ##STR6## wherein: n=1-4
A second patent, U.S. Pat. No. 4,372,960, issued Feb. 8, 1983 to L'Italien disclosed a series of quaternary derivatives of N-(substituted-aminoalkyl)-2-oxo-1-pyrrolidine acid amides. These compounds of structural formula 5 are disclosed as being useful in the treatment of senility, memory enhancement and amnesia reversal. ##STR7## wherein: n=1-4
European Patent Application No. 89,900, published Sept. 28, 1983 concerns a series of piperazine derivatives of formula 6 which are disclosed as drugs especially useful in the treatment of cerebral vascular disturbances in the elderly. ##STR8## wherein: R is hydrogen or C.sub.1-3 alkyl; and
Malawska, et al., "Synthesis and Pharmacological Properties of Some 2-Pyrrolidinone Mannich Bases" in Polish Journal of Pharmacology, 1982, 34, 373-382, disclose a series of compounds of which one subclass is represented by structural formula 7. These compounds reportedly displayed analgesic properties as well as weak anti-inflammatory action. ##STR9## wherein X is hydrogen or chlorine.
All of the above referenced compounds differ from the series of compounds of the instant invention in which B is a 2-pyrimidinyl heterocyclic ring as compared with the reference compounds wherein B is alkyl, aryl, or aralkyl. The following reference compounds are even less related than the foregoing.
A large number of psychotropic compounds with structures corresponding to formula 8 have been disclosed by Wu, Temple, New, and co-workers. ##STR10## wherein n is from 2 to 6. These compounds of structure 8 and similar analogs, however, are N-substituted cyclic imide rings, e.g. succinimides, glutarimides, etc. and easily distinguished from the compounds of the instant invention.
See:
Similarly, the compounds disclosed by Okazaki, et al., in U.S. Pat. No. 4,420,481 issued Dec. 13, 1983, (cf: structural formula 9); and Weber, et al. in U.S. Pat. No. 4,216,216, issued Aug. 5, 1980, (cf: structural formula 10); ##STR11## can be distinguished from the compounds of the instant invention by virtue of these structures lacking both a lactam ring as well as a 2-pyrimidinyl ring moiety.
In summary, there are no teachings in the art which would make the specific compounds comprising the instant invention anticipated or obvious.